This invention is directed to novel vanilloid receptor VR1 ligands. More particularly, this invention relates to novel quinoline-derived amides that are potent antagonists or agonists of VR1 and exhibit activity in animal models of hyperalgesia and colitis, and are useful for the treatment and prevention of pain conditions in humans including arthritis, and for the treatment of irritable-bowel syndrome and associated conditions.
Noxious chemical, thermal and mechanical stimuli excite peripheral nerve endings of small diameter sensory neurons (nociceptors) in sensory ganglia (e.g., dorsal root, nodose and trigeminal ganglia) and initiate signals that are perceived as pain. These neurons are crucial for the detection of harmful or potentially harmful stimuli (heat) and tissue damage (local tissue acidosis and/or stretch) that arise from changes in the extracellular space during inflammatory or ischaemic conditions (Wall, P. D., and Melzack, R., Textbook of Pain, 1994, New York: Churchill Livingstone). Nociceptors transduce noxious stimuli into membrane depolarization that triggers action potential, conducts the action potential from the sensory sites to the synapses in the CNS, and conversion of action potentials invokes a perception of pain, discomfort, and appropriate mechanical/physical protective reflexes. At the molecular level, nociception is carried out by ion channels or receptors. Plant derived vanilloid compounds (capsaicin and its ultrapotent analog, resiniferatoxin, etc.) are known to selectively depolarize nociceptors and elicit sensations of burning pain—the sensation that is typically obtained by hot chili peppers. Therefore, capsaicin mimics the action of physiological/endogenous stimuli that activates the “nociceptive pathway”. Recent advances in pain biology have identified receptors for vanilloids, protons (i.e., acidic solutions), and for heat. Because nociceptors are involved with unwanted pain and inflammatory conditions in human beings and animals, modulation of their nociceptive pathway is important in palliative and other therapies.
U.S. Pat. No. 4,786,644 discloses 1-aryl-3-quinoline carboxamides as analgesics and antiinflammatory agents. This patent, however, does not disclose or suggest the compounds, compositions or methods of the present invention.
Thus, there is a need for potent modulators of VR, and in particular, for novel quinoline-derived amides that exhibit potent binding affinity for the human and rat VR1 ion channel. There is also a need for novel quinoline-derived amides that act as potent functional antagonists and/or agonists of the human and rat VR1 ion channel. Finally, there is a need for novel quinoline-derived amides that bind with high affinity to VR1 and also act as potent functional antagonists of the human and rat VR1 ion channel.